PROJECT SUMMARY Inheritance of the apolipoprotein E4 (apoE4) gene is the strongest genetic risk factor identified to date for late onset Alzheimer?s disease (AD). Although the mechanisms by which apoE4 affects the development of AD are not completely understood, compelling evidence indicates that the pathogenic effects of apoE4 are mediated by lipid-related pathways. Compared with the more common apoE3 isoform, apoE4 exhibits deficiency in lipidation and formation of high density lipoproteins (HDL) in the brain. Genetic and pharmacological manipulations of apoE lipidation/HDL formation pathways have been shown to modulate cognitive function and neuropathology in animal models of AD. However, adverse side effects associated with those treatments are of significant concern. In the present proposal, we attempt to repurpose a unique, well characterized, and clinically tested HDL mimetic peptide to reverse apoE4 lipidation deficiency and AD-related neuropathology. This small synthetic peptide consists of 18 amino acids and has no direct sequence homology to natural proteins but mimics the unique lipid-interacting structure contained in HDL-associated apolipoproteins. Previous studies have demonstrated that this peptide possesses vascular protective properties as HDL. It has advanced into early human clinical trials for cardiovascular disease and showed no safety concerns. In preliminary studies, we have found that this peptide promotes cellular cholesterol efflux, enhances apoE secretion and lipidation from astrocytes and microglia, and counteracts amyloid ? (A?)-induced suppression on apoE secretion and lipidation by glial cells. In addition, this peptide inhibits A? aggregation, promotes the transport of A? across a cellular model of human blood-brain barrier (BBB), and efficiently penetrates the BBB in mice. Thus, we hypothesize that treatment with this unique peptide can rescue brain apoE4 lipidation and functional deficits and mitigate apoE4-associated neuropathology in AD. This hypothesis will be tested by two specific aims in human apoE4-targeted replacement (TR) mice, which recapitulate functional deficits of apoE4 carriers in humans, compared with human apoE3-TR mice in the absence or presence of A? pathology. Positive results from this preclinical study are expected to have a significant overall impact in the research field of AD as this project will provide a proof of concept for developing innovative HDL-based therapeutic approaches targeting apoE4 pathological mechanisms.